US2022087989A1PendingUtilityA1
Aryl-aniline and heteroaryl-aniline compounds for treatment of skin cancers
Assignee: NFLECTION THERAPEUTICS INCPriority: Nov 20, 2018Filed: Nov 20, 2019Published: Mar 24, 2022
Est. expiryNov 20, 2038(~12.4 yrs left)· nominal 20-yr term from priority
A61P 35/00A61K 31/4375A61K 31/4025A61K 31/381A61K 31/4365A61K 31/437A61K 31/44A61K 31/42A61K 31/40A61K 31/337A61K 31/397A61K 31/277A61K 31/422A61K 31/4535
54
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Claims
Abstract
Provided herein are compounds and pharmaceutical compositions thereof for treating a skin cancer in a subject in need thereof, wherein the compound is according to any one of formula (I), (II), (III), (IV), and (V): wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 2a , R 13 , R 13a , R 23 , R 23a , R 23b , R 33 , R 33a , R 33b , R 43 , R 43a , R 51 , R 53 , R 53a , R 53b , bond “a”, and subscript n are described herein.
Claims
exact text as granted — not AI-modified1 . A method of treating or preventing a skin cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of formula (I), (II), (III), (IV), and (V):
or a N-oxide, stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is —CR 13b or N; X 2 is C 1 -C 6 alkyl; X 3 is S or O;
subscript n is an integer from 0 to 2;
bond “a” is a single or double bond;
R 1 is —OR 4 , —NR 5 R 5a , —N(OR 5b )R 5a , or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R 6 ;
R 2 is halo, C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 2a is halo or C 1 -C 6 alkyl;
R 4 , R 5 , and R 5b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)amino-C 1 -C 6 alkyl, heterocycloalkyl, heterocycloalkyl-C 1 -C 6 alkyl, or R 7 —C(O)—C 1 -C 6 alkyl, wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 ;
R 5a is hydrogen or C 1 -C 6 alkyl;
each R 6 is independently halo, hydroxy, oxo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 haloalkyl, amino, C 1 -C 6 alkylamino, di-(C 1 -C 6 alkyl)amino, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, or di-(C 1 -C 6 alkyl)amino-C 1 -C 6 alkyl;
R 7 is hydroxy, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di-(C 1 -C 6 alkyl)amino, hydroxyamino, or N—C 1 -C 6 alkyl hydroxyamino;
R 13 , R 13a , and R 13b are each independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 23 , R 23a , and R 23b are each independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkoxy;
R 33 , R 33a , and R 33b are each independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkoxy;
R 43 is cyano, —C(O)NR 48 R 48a , or —C(O)R 46 ;
R 43a is hydrogen, halo, C 1 -C 6 alkyl; or
R 43 and R 43a together form —CH 2 CH 2 C(O)— or —CH 2 CH 2 CH 2 C(O)—, each of which is unsubstituted or substituted with one or two R 49 ;
R 46 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or heterocycloalkyl;
R 48 and R 48a are independently hydrogen or C 1 -C 6 alkyl; and
each R 49 is independently C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl;
R 51 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)amino-C 1 -C 6 alkyl, heterocycloalkyl, heterocycloalkyl-C 1 -C 6 alkyl, R 7 —C(O)—C 1 -C 6 alkyl, or —OR 54 , wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 ;
each R 53 is independently halo or C 1 -C 6 alkyl;
R 53a and R 53b are each independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
R 54 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)amino-C 1 -C 6 alkyl, heterocycloalkyl, heterocycloalkyl-C 1 -C 6 alkyl, or R 7 —C(O)—C 1 -C 6 alkyl, wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 .
2 . The method of claim 1 , wherein the compound has formula (Ia) or (Ib):
3 - 8 . (canceled)
9 . The method of claim 1 , wherein X 2 of formula (II) is C 1 -C 3 alkyl.
10 . The method of claim 1 , wherein X 2 is methyl.
11 . The method of claim 1 , wherein R 23 , R 23a , and R 23b are each independently hydrogen, halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
12 . The method of claim 1 , wherein R 23 and R 23b are each hydrogen and R 23a is halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
13 . The method of claim 1 , wherein R 23 and R 23b are each hydrogen and R 23a is fluoro, methyl, or methoxy.
14 . The method of claim 1 , wherein R 23 , R 23a , and R 23b are each hydrogen.
15 . The method of claim 1 , wherein the compound has formula (IIIa) or (IIIb):
16 - 21 . (canceled)
22 . The method of claim 1 , wherein the compound has the formula selected from the group consisting of:
23 - 37 . (canceled)
38 . The method of claim 1 , wherein R 1 is —NR 5 R 5a and R 5 is —OR 5b .
39 . The method of claim 1 , wherein R 1 is —N(OR 5b )R 5a ; R 5b is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)amino-C 1 -C 6 alkyl, heterocycloalkyl, heterocycloalkyl-C 1 -C 6 alkyl, or R 7 —C(O)—C 1 -C 6 alkyl; R 7 is hydroxy, C 1 -C 6 alkoxy, amino, or hydroxyamino; and each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 and each R 6 is independently hydroxy or C 1 -C 6 alkyl.
40 . The method of claim 1 , wherein —OR 5b is selected from the group consisting of:
41 . The method of claim 1 , wherein R 1 is —NR 5 R 5a or —N(OR 5b )R 5a , and R 5a is hydrogen.
42 - 45 . (canceled)
46 . The method of claim 1 , wherein the compound has formula (Va) or (Vb):
47 - 56 . (canceled)
57 . The method of claim 1 , wherein R 2 is halo, C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, or C 2 -C 6 alkynyl.
58 . The method of claim 1 , wherein R 2 is halo.
59 . The method of claim 1 , wherein R 2 is iodo.
60 - 61 . (canceled)
62 . The method of claim 1 , wherein R 2 is —S—C 1 -C 6 alkyl.
63 . The method of claim 1 , wherein R 2 is —SCH 3 .
64 . The method of claim 1 , wherein R 2 is C 2 -C 6 alkynyl.
65 . The method of claim 1 , wherein R 2 is acetylenyl.
66 . The method of claim 1 , wherein R 2a is halo.
67 . The method of claim 1 , wherein R 2a is fluoro.
68 . The method of claim 1 , wherein R 2a is C 1 -C 6 alkyl.
69 . The method of claim 1 , where R 2a is methyl.
70 . The method of claim 1 , wherein the compound is selected from the group consisting of Compounds in Tables 1 to 5.
71 . The method of claim 1 , wherein the compound is administered with a pharmaceutically acceptable carrier in a pharmaceutical composition.
72 . The method of claim 1 , wherein the skin cancer is a cutaneous squamous-cell carcinoma.
73 . The method of claim 1 , wherein the skin cancer is a MEK-inhibitor responsive or MEK-mediated cutaneous squamous-cell carcinoma.
74 . The method of claim 1 , wherein the cutaneous squamous-cell carcinoma is associated with activation of p-ERK.
75 . The method of claim 1 , wherein the compound having any one of formulae (I) to (V) or the pharmaceutical composition thereof is administered topically, subcutaneously, intradermally, or intralesionally.
76 . The method of claim 1 , wherein the compound having any one of formulae (I) to (V) or the pharmaceutical composition thereof is administered as a lotion, a spray, an ointment, a cream, a gel, a paste, and a patch.Cited by (0)
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